Epilepsy and brain inflammation

During the last decade, experimental research has demonstrated a prominent role of glial cells, activated in brain by various injuries, in the mechanisms of seizure precipitation and recurrence. In particular, alterations in the phenotype and function of activated astrocytes and microglial cells have been described in experimental and human epileptic tissue, including modifications in potassium and water channels, alterations of glutamine/glutamate cycle, changes in glutamate receptor expression and transporters, release of neuromodulatory molecules (e.g. gliotransmitters, neurotrophic factors), and induction of molecules involved in inflammatory processes (e.g. cytokines, chemokines, prostaglandins, complement factors, cell adhesion molecules) (Seifert et al., 2006; Vezzani et al., 2011; Wetherington et al., 2008). In particular, brain injury or proconvulsant events can activate microglia and astrocytes to release a number of proinflammatory mediators, thus initiating a cascade of inflammatory processes in brain tissue. Proinflammatory molecules can alter neuronal excitability and affect the physiological functions of glia by paracrine or autocrine actions, thus perturbing the glioneuronal communications. In experimental models, these changes contribute to decreasing the threshold to seizures and may compromise neuronal survival (Riazi et al., 2010; Vezzani et al., 2008). In this context, understanding which are the soluble mediators and the molecular mechanisms crucially involved in glio–neuronal interactions is instrumental to shed light on how brain inflammation may contribute to neuronal hyperexcitability in epilepsy. This review will report the clinical observations in drug-resistant human epilepsies and the experimental findings in adult and immature rodents linking brain inflammation to the epileptic process in a causal and reciprocal manner. By confronting the clinical evidence with the experimental findings, we will discuss the role of specific soluble inflammatory mediators in the etiopathogenesis of seizures, reporting evidence for both their acute and long term effects on seizure threshold. The possible contribution of these mediators to co-morbidities often described in epilepsy patients will be also discussed. Finally, we will report on the anti-inflammatory treatments with anticonvulsant actions in experimental models highlighting possible therapeutic options for treating drug-resistant seizures and for prevention of epileptogenesis.